We previously reported that exercise training drives enhanced agonist-stimulated hydrogen peroxide (H2O2) levels and restores endothelium-dependent dilation via an increased reliance on H2O2 in arterioles isolated from ischemic porcine hearts. In this study, we tested the hypothesis that exercise training would correct impaired H2O2-mediated dilation in coronary arterioles isolated from ischemic myocardium through increases in protein kinase G (PKG) and protein kinase A (PKA) activation and subsequent colocalization with sarcolemmal K+ channels. Female adult Yucatan miniature swine were surgically instrumented with an Ameroid constrictor around the proximal left circumflex coronary artery, gradually inducing a collateral-dependent vascular bed. Arterioles (~125 µm) supplied by the left anterior descending artery served as nonoccluded control vessels. Pigs were separated into exercise (treadmill; 5 days/week for 14 weeks) and sedentary groups. Collateral-dependent arterioles isolated from sedentary pigs were significantly less sensitive to H2O2-induced dilation compared with nonoccluded arterioles, whereas exercise training reversed the impaired sensitivity. Large conductance calcium-activated potassium (BKCa) channels and 4AP-sensitive voltage-gated (Kv) channels contributed significantly to dilation in nonoccluded and collateral-dependent arterioles of exercise-trained but not sedentary pigs. Exercise training significantly increased H2O2-stimulated colocalization of BKCa channels and PKA, but not PKG, in smooth muscle cells of collateral-dependent arterioles compared with other treatment groups. Taken together, our studies suggest that with exercise training, nonoccluded and collateral-dependent coronary arterioles better utilize H2O2 as a vasodilator through increased coupling with BKCa and 4AP-sensitive Kv channels; changes that are mediated in part by enhanced colocalization of PKA with BKCa channels.

The objective of this study was to determine downstream cellular signaling pathways by which exercise training promotes H2O2‐mediated dilation in arterioles distal to chronic coronary artery occlusion. We tested the hypothesis that exercise training would correct impaired H2O2‐mediated dilation in collateral‐dependent arterioles through enhanced coupling of H2O2 with voltage‐gated K+ (Kv) and large‐conductance, calcium‐dependent K+ (BKCa) channels. Yucatan miniature swine were surgically instrumented with an Ameroid constrictor around the proximal left circumflex coronary artery, which gradually induced occlusion and created a collateral‐dependent vascular bed. Arterioles from the left anterior descending artery region served as nonoccluded control vessels. Pigs were separated into two groups: one that underwent a progressive exercise training program (treadmill run; 5 days/week for 14 weeks) and another that remained sedentary and was limited to normal pen activity. Collateral‐dependent arterioles from sedentary pigs were significantly less sensitive to H2O2‐induced dilation compared with nonoccluded arterioles (EC50: ‐4.55 ± 0.15 vs. ‐4.91 ± 0.15 log M, respectively; P<0.05), whereas this difference was eliminated after completion of the exercise training regimen when collateral‐dependent and nonoccluded arterioles responded similarly to H2O2 (EC50: ‐4.86 ± 0.16 vs. ‐4.95 ± 0.18 log M, respectively). H2O2‐mediated dilation in nonoccluded or collateral‐dependent arterioles from sedentary animals was not altered by inhibitors of Kv (4‐aminopyridine; 1 mM) or BKCa (iberiotoxin; 100 nM) channels. In contrast, after exercise training, Kv channels contributed significantly to dilation in nonoccluded arterioles and both Kv and BKCa channels played a significant role in dilation of collateral‐dependent arterioles. Interestingly, the contribution of Kv and BKCa channels to basal tone was not altered by occlusion or exercise training, suggesting similar availability of these channels in nonoccluded and collateral‐dependent arterioles of sedentary and exercise‐trained pigs. Immunoblot analysis was performed to assess levels of PKG dimerization, a potential mediator between H2O2 and K+ channels. These studies revealed that H2O2 treatment significantly increased PKG dimerization in all artery treatment groups, and this effect was significantly greater in nonoccluded compared with collateral‐dependent arteries from sedentary pigs, but not different after exercise training. Taken together, our studies suggest that impaired H2O2‐mediated vasodilation may be in part attributable to attenuated PKG dimerization in collateral‐dependent arterioles of sedentary pigs. However, while exercise training appeared to correct impaired H2O2‐mediated dilation via enhanced coupling to K+ channel activation, exercise‐induced changes in PKG dimerization did not appear to play a role.

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Begin with a short sentence or two with background on the topic. Please include a PURPOSE: describing the intent of the study. METHODS: how the study was conducted. RESULTS: findings of the study and CONCLUSION: Reference lists are not generally included.Current published data are inconclusive regarding whether DXA body composition measures of fat, lean, and regional fat mass are predictive of other CVD risk factors. PURPOSE: To determine if DXA measures can be used in a cardiovascular risk-predictive manner to indicate unhealthy levels of circulating lipoproteins in firefighters. METHODS: 256 male firefighters (age=35±10; ht=179±6.6 cm; wt=94±16 kg; BMI=29.9±4.6; fat mass=27.5±10.4 kg; lean mass=63±7.5 kg; gynoid%fat=28.7±6.5%; android%fat=36±11.3%; glucose=85±12.9 mg/dL; SBP=128±9 mmHg) underwent an annual cardiovascular risk profile screening and DXA scan; resting BP was also measured. We drew fasting blood samples, analyzed by a clinically certified lab, to determine glucose, HDL, LDL, total cholesterol, and triglycerides. Statistics included simple statistics and Pearson's correlations. RESULTS: Table (*=p<.01) CONCLUSIONS: Though the correlations were statistically significant, none of the DXA body composition measures explained a physiologically relevant portion of the variance in the CVD risk markers measured. We suggest that factors other than body fat contribute to lipid and blood pressure profiles in firefighters, a population at high risk for CVD.

In coronary artery disease (CAD), the ability of the coronary circulation to deliver blood to meet oxygen demands of the heart is often impaired. Exercise training has been established to mitigate the negative effects of CAD by preserving reactivity of the coronary microcirculation. We have previously reported that exercise increases the contribution of hydrogen peroxide (H2O2) to enhanced endothelium‐dependent vasodilation in collateral‐dependent coronary arterioles. Others have shown that cGMP‐dependent protein kinase (PKG) can be activated via oxidation by H2O2, inducing dimer formation. The PKG dimer has been shown to act on substrates, such as K+ channels, to contribute to vascular smooth muscle relaxation and vasodilation. In the current study, we tested the hypothesis that exercise training‐enhanced H2O2‐induced vasodilation is mediated through enhanced PKG dimerization and subsequent activation of Kv and BKca channels in coronary arterioles isolated from ischemic myocardium. An ameroid occluder was surgically placed on the proximal left circumflex coronary artery of female Yucatan miniature swine to induce gradual occlusion while the left anterior descending artery was left unoccluded to serve as a control. Eight weeks postoperatively, pigs were assigned to sedentary (n=14) or exercise training (n=13; progressive treadmill training for 13 weeks) regimens. Coronary arterioles (75–150 μm) and small arteries (250–400 um) were isolated from myocardium of the left circumflex and left anterior descending regions. Immunoblot analysis indicated that H2O2 induced PKG dimer formation in both porcine coronary arterioles and small arteries. Chronic coronary artery occlusion appeared to diminish H2O2‐mediated PKG dimer formation in collateral‐dependent arterioles and the reduced dimerization persisted with exercise training. H2O2‐mediated vasodilation tended to be impaired in arterioles isolated from the collateral‐dependent regions of sedentary pigs and was partially restored with exercise training. It also appears that both Kv and BKCa channels contributed to H2O2‐mediated dilation after exercise training. Our data demonstrate that H2O2 stimulates PKG dimer formation in both porcine coronary arterioles and small arteries. Contrary to our hypothesis, H2O2‐induced PKG dimerization is not enhanced by exercise training in either nonoccluded or collateral‐dependent arterioles. However, both Kv and BKCa channels appear to contribute to exercise training‐enhanced H2O2‐mediated dilation in collateral‐dependent coronary arterioles. Support or Funding Information National Institutes of Health R01‐HL139903